Approximately 3 million people visit health care providers each year for kidney stones. Of those 3 million patients, in the United States more than one half million suffer from kidney stone-related conditions. Kidney stones are a very common and painful urinary tract disorder. The most common type of stone contains calcium in combination with either oxalate or phosphate, in which approximately 70% is calcium oxalate. (Tsujihata, M. (2008) Mechanism of calcium oxalate renal stone formation and renal tubular cell injury, Int J Urol 15, 115-120; Daudon, M., Dore, J. C., Jungers, P., and Lacour, B. (2004) Changes in stone composition according to age and gender of patients: a multivariate epidemiological approach, Urol Res 32, 241-247.) Many disease states are associated with an excess quantity of oxalate in the body including: primary hyperoxaluria, secondary hyperoxaluria, autism, vulvodynia, oxalosis associated with end-stage renal disease, cardiac conductance disorders, Crohn's disease, inflammatory bowel disease, colitis, urolithiasis, oxalosis associated with end-stage renal disease, sarcoidosis, asthma, COPD, fibromyalgia, Zellweger syndrome, bariatric surgery and other enteric disease states.
Oxalate is normally produced in plants, and is primarily found in leaves, nuts, fruits and barks. In food products, oxalate is found in high levels particularly in plant foods including: vegetables, cereal grains, nuts, beans and beverages. A typical daily intake of oxalate is between 80-120 mg/day, but can range from 44-350 mg/day. Dietary oxalate may form sodium, potassium or calcium salts in food.
Oxalate may be absorbed throughout the entire gastrointestinal tract (GI tract) including the stomach, and the small and large intestines. Therefore, removal of dietary oxalate in these organs is effective in preventing oxalate absorption. Absorption of dietary oxalate contributes to 10-70% of urinary oxalate secretion, likely a crucial contribution to urinary calcium oxalate supersaturation. (Holmes, R. P., Goodman, H. O., and Assimos, D. G. (2001) Contribution of dietary oxalate to urinary oxalate excretion, Kidney Int 59, 270-276.) It is believed that calcium oxalate supersaturation is the determining driving force of calcium oxalate stone formation. Therefore, by reducing calcium oxalate supersaturation, the risk of stone formation will likely be significantly decreased.
There are very few, if any, treatment strategies known to significantly decrease the risk of stone formation by reducing or eliminating the absorption of dietary oxalate in the system. One way to limit dietary oxalate absorption would be to orally administer oxalate degrading enzymes which come into contact with the stomach and the small and large intestines. The challenge in providing such treatment is the harsh acidic stomach environment, making it difficult for an enzyme to survive and function at a low pH and in a high pepsin activity environment. The small and large intestines also provide a challenging environment for the survival of an enzyme due to the high levels of trypsin and chymotrypsin activity. The pH in the stomach is affected by several factors including individual stomach health-related conditions, and quantity and substance of meals. These factors may result in a broad stomach pH range between 1.9-5.5. The pH in the human stomach is non-homogenous due to the presence of acid pockets. Hence, it is critical to find an oxalate-degrading enzyme that is stable and potent within this acidic pH range to be an effective treatment for humans. Additionally, the oxalate degrading enzyme must be stable within a pH range of 5.5-8.0 that can withstand the conditions of the intestinal tract. The oxalate degrading enzyme must be protected from pepsin digestion in the stomach as well as from trypsin and chymotrypsin in the small and large intestines.